NLRP3 haploinsufficiency unmasks a compensatory NLRP1-NLRP3 interaction that drives accelerated aging in mice

The NLRP3 inflammasome has been implicated in a wide range of human diseases, including cardiovascular, metabolic, neurodegenerative (such as Alzheimer’s disease), and other age-related conditions. This has positioned NLRP3 as a promising pharmacological target. Numerous studies have shown that complete NLRP3 ablation can prevent or mitigate these diseases. However, total elimination of NLRP3 is not a feasible therapeutic strategy for the millions of patients affected by these degenerative disorders. Consequently, drug development efforts have focused on partial inhibition of NLRP3 using compounds that reduce its expression or activity. Paradoxically, although many studies have used Nlrp3 knockout mouse models, Nlrp3 haploinsufficient mice—more representative of the effects of pharmacological inhibition—are rarely included and remain poorly characterized. Here, we report the long-term effects of Nlrp3 haploinsufficiency during aging. Although no overt differences were observed in early life, by 16 months of age, Nlrp3 heterozygous mice exhibited signs of accelerated inflammatory aging, driven by compensatory overexpression of NLRP1. Mechanistic studies provide evidence of a previously unidentified interaction between NLRP1 and NLRP3, forming a hybrid inflammasome that drives NLRP1-mediated inflammatory overactivation when NLRP3 expression is reduced. Accordingly, anti-inflammatory treatment provided notable but moderate improvement of the inflammatory phenotype, whereas genetic inhibition of Nlrp1 more consistently reduced inflammation and extended health span. Our findings reveal a previously unidentified compensatory interaction between NLRP1 and NLRP3 and suggest that multiinflammasome inhibition may offer a more effective strategy for treating aging and age-related diseases.

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Publication Details

Journal
Science Advances
Published
2026-06-26
DOI
https://doi.org/10.1126/sciadv.aec9499
Primary Topic
Inflammasome and immune disorders
Type
article
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article

NLRP3 haploinsufficiency unmasks a compensatory NLRP1-NLRP3 interaction that drives accelerated aging in mice

Joaquin Tamargo‐Azpilicueta, Antonio Astorga-Gamaza, Evon Low, Abbas Ishaq et al.
Science Advances
Inflammasome and immune disorders
article

NLRP3 haploinsufficiency unmasks a compensatory NLRP1-NLRP3 interaction that drives accelerated aging in mice

Joaquin Tamargo‐Azpilicueta, Antonio Astorga-Gamaza, Evon Low, Abbas Ishaq, Amparo Luque‐Sierra, Elísabet Alcocer‐Gómez, Félix Elortza, Juan M. Suárez-Rivero, Mario D. Cordero, Javier Oroz, Jesús Ruı́z-Cabello, Irene Díaz‐Moreno, Łukasz A. Joachimiak, Alejandra Guerra‐Castellano, Thomas von Zglinicki, Sofia Bali, Mikel Azkargorta, Franz Martı́n, Alberto Sanz, Rosa Antón, Inés Muela-Zarzuela
article en

Abstract

The NLRP3 inflammasome has been implicated in a wide range of human diseases, including cardiovascular, metabolic, neurodegenerative (such as Alzheimer’s disease), and other age-related conditions. This has positioned NLRP3 as a promising pharmacological target. Numerous studies have shown that complete NLRP3 ablation can prevent or mitigate these diseases. However, total elimination of NLRP3 is not a feasible therapeutic strategy for the millions of patients affected by these degenerative disorders. Consequently, drug development efforts have focused on partial inhibition of NLRP3 using compounds that reduce its expression or activity. Paradoxically, although many studies have used Nlrp3 knockout mouse models, Nlrp3 haploinsufficient mice—more representative of the effects of pharmacological inhibition—are rarely included and remain poorly characterized. Here, we report the long-term effects of Nlrp3 haploinsufficiency during aging. Although no overt differences were observed in early life, by 16 months of age, Nlrp3 heterozygous mice exhibited signs of accelerated inflammatory aging, driven by compensatory overexpression of NLRP1. Mechanistic studies provide evidence of a previously unidentified interaction between NLRP1 and NLRP3, forming a hybrid inflammasome that drives NLRP1-mediated inflammatory overactivation when NLRP3 expression is reduced. Accordingly, anti-inflammatory treatment provided notable but moderate improvement of the inflammatory phenotype, whereas genetic inhibition of Nlrp1 more consistently reduced inflammation and extended health span. Our findings reveal a previously unidentified compensatory interaction between NLRP1 and NLRP3 and suggest that multiinflammasome inhibition may offer a more effective strategy for treating aging and age-related diseases.

Science AdvancesVol. 12(26)
Ikerbasque (ES), Universidad Complutense de Madrid (ES), Instituto de Salud Carlos III (ES), CIC biomaGUNE (ES), Centro de Investigación Biomédica en Red Diabetes y Enfermedades Metabólicas Asociadas (ES), Centro de Investigación Biomédica en Red de Enfermedades Respiratorias (ES), CIC bioGUNE (ES), Instituto de Química Médica (ES), Centro Andaluz de Biología Molecular y Medicina Regenerativa (ES), Instituto de Investigaciones Químicas (ES), Instituto de Química Orgánica General (ES), University of Glasgow (GB), Universidad de Sevilla (ES), Newcastle University (GB), The University of Texas Southwestern Medical Center (US), Universidad Pablo de Olavide (ES)
Junta de Andalucía, Fundación Contra la Hipertensión Pulmonar, Agencia Estatal de Investigación
Good health and well-being
Openalex Percentile: Top 11%
Inflammasome and immune disorders
DOIOpen Access PDFOpenAlex
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